Juliet Daniel, Ph.D.
Cancer Biology, Cadherin-Catenin mediated Cell adhesion and Signaling, POZ Transcription Factors
Our research goal is to understand the cellular and molecular basis of E-cadherin-mediated adhesion in normal cell growth, development and tumourigenesis. The primary epithelial cell-cell adhesion system involving E-cadherin and its catenin cofactors a-, b-, g- and p120ctn, is perturbed in ~50% of human metastatic tumours, and this correlates with the invasive phenotype. Interestingly, the catenins also function as transcriptional regulators of genes involved in tumourigenesis. My laboratory focuses on the transcription factor Kaiso that was first identified as a specific binding partner for the catenin p120ctn, which is aberrantly expressed or absent in human breast, colon and skin carcinomas. Kaiso is a novel member of the POZ-zinc finger family of transcription factors implicated as oncoproteins or tumor suppressors, and currently it is the only known POZ protein with bi-modal DNA-binding and transcriptional repression activity; Kaiso recognizes a sequence-specific consensus, TCCTGCNA, or methylated CpG-dinucleotides.
- Chaudhary R, Pierre CC, Nanan K, Wojtal D, Morone S, Pinelli C, Wood GA, Robine S, Daniel JM. (2013) The POS-ZF transcription factor Kaiso (ZBTB33) induces inflammation and progenitor cell differentiation in the murine intestine. PLoS One 8:e74160.
- Donaldson NS, Pierre CC, Anstey MI, Robinson SC, Weerawardane S and Daniel JM. Kaiso represses the cell cycle gene cyclin D1 via sequence-specific and methyl-CpG-dependent mechanisms. (2012) PLoS ONE 7(11): e50398.
- Vermeulen JF, van de Ven RAH, Ercan C, van der Groep P, van der Wall E, Bult P, Christgen M, Lehmann U, Daniel JM, van Diest PJ and Derksen PWB. Nuclear Kaiso Expression is Associated with High Grade and Triple-Negative Invasive Breast Cancer. (2012) PLoS One. 7:e37864
- Nanan KK and Daniel JM. ZBTB33 (Mus musculus). Transcription Factor Encyclopedia.(2010)
- Donaldson NS, Nordgaard CL, Pierre CC, Kelly KF, Robinson S, Swystun L, Henriquez R, Graham M and Daniel JM. Kaiso regulates Znf131-mediated transcriptional activation. (2010) Exp. Cell Res. 316:1692-1705
- Brown ST, Kelly KF, Daniel JM and Nurse CA. Hypoxia inducible factor (HIF)-2α is required for the development of the catecholaminergic phenotype of sympathoadrenal cells. (2009) J. Neurochem. 110:622-630
- Ferber EC, Kajita M, Wadlow A, Tobiansky L, Niessen C, Ariga H, Daniel J, Fujita Y. A role for the cleaved cytoplasmic domain of E-cadherin in the nucleus. (2008) J. Biol. Chem. 283:12691-12700
- Donaldson NS, Daniel Y, Kelly KF, Graham M and Daniel JM. Nuclear trafficking of the novel POZ-ZF protein Zn131. (2007) BBA- Mol. Cell Res.1773: 546-555.
- Daniel JM. Dancing in and out of the nucleus: p120ctn and the transcription factor Kaiso. (2007) BBA- Molecular Cell Research Special issue “The p120-Catenin Protein Family”. 1773: 59-68. (Guest Co-editor with Dr. Alpha Yap). Kelly KF and Daniel JM. POZ for Effect – POZ-ZF Transcription Factors in Cancer and Development. (2006) Trends Cell Biol. 16: 578-587.
- Defossez PA, Kelly KF, Filion G, Magdinier F, Menoni H, Nordgaard CL,Daniel JM and Gilson E. The human enhancer-blocker CTCF interacts with the transcription factor Kaiso. (2005) J. Biol. Chem. 280:43017-43023.
- Spring CM, Kelly KF, O’Kelly I, Graham M, Crawford HC and Daniel JM. The catenin p120ctn inhibits Kaiso-mediated Transcriptional Repression of the beta-catenin/TCF target gene matrilysin. (2005) Exp. Cell Res. 305:253- 265.
- Kim SW, Park JI, Spring CM, Sater AK, Ji H, Otchere AA, Daniel JM and McCrea PD. Non-Canonical Wnt signals are modulated by the Kaiso transcriptional repressor and p120-catenin. (2004) Nat. Cell Biol. 6: 1212-1220.Kelly KF, Otchere AA, Graham M and Daniel JM. Nuclear Import of the BTB/POZ Transcriptional Regulator Kaiso. (2004) J. Cell Sci. 117: 6143-6152.
- Rodova M, Kelly KF, VanSaun M, Daniel JM and Werle MJ. Regulation of the Rapsyn promoter by Kaiso and delta-catenin. (2004) Mol. Cell. Biol. 24: 7188-7196.
- Kelly KF, Spring CM, Otchere AA and Daniel JM. NLS-dependent nuclear localization of p120ctn is necessary to relieve Kaiso-mediated transcriptional repression. (2004) J. Cell Sci. 117: 2675-2686
- Daniel JM, Spring CM, Reynolds AB, Crawford HC and Baig A. The p120ctn-binding partner Kaiso is a bi-modal DNA-binding protein that recognizes both a sequence-specific consensus and methylated CpG dinucleotides. (2002) Nucleic Acids Res. 30: 2911-2919.
- Kim SW, Fang X, Ji L, Paulson AF, Daniel JM, Ciesiolka M, van Roy F and McCrea PD. Isolation and characterization of XKaiso, a transcriptional repressor that associates with the catenin Xp120ctn in Xenopus laevis. (2002) J. Biol. Chem. 277: 8202-8208.
- Daniel JM, Ireton RC and Reynolds AB. Monoclonal antibodies to Kaiso, a novel transcription factor and p120ctn-binding protein. (2001) Hybridoma 20: 159-166
- Thoreson MA, Anastasiadis PZ, Daniel JM, Ireton RC, Wheelock MJ, Johnson KR, Hummingbird DK and Reynolds AB. Selective uncoupling of p120ctn from E-cadherin disrupts strong adhesion. (2000) J. Cell Biol. 148: 189-201.
- Mariner DJ, Sirotkin H, Daniel JM, Lindman BR, Mernaugh RL, Patten AK, Thoreson MA, Kucherlapati R and Reynolds AB. Production and characterization of monoclonal antibodies to ARVCF. (1999) Hybridoma 18: 343-349.
- Daniel JM and Reynolds AB. The catenin p120ctn interacts with Kaiso, a novel BTB/POZ domain zinc finger transcription factor. (1999) Mol. Cell. Biol. 19: 3614-3623.
- Daniel JM and Reynolds AB. Tyrosine phosphorylation and cadherin/catenin function. (1997) Bioessays 19: 883-891. Reynolds AB, Jenkins NA, Gilbert DJ, Copeland NG, Shapiro DN, Wu J and Daniel JM. The gene encoding p120cas, a novel catenin, localizes on human chromosome 11q11 (ctnND) and mouse chromosome 2 (Catns). (1996) Genomics 31: 127-129.
- Reynolds AB, Zhang Z, Wu J, Daniel JM and Mo Y-Y. The novel catenin p120cas binds classical cadherins and induces an unusual morphological phenotype in NIH 3T3 fibroblasts. (1996) Exp. Cell Res. 225: 328-337.
- Daniel JM and Reynolds AB. The tyrosine kinase substrate p120cas binds directly to E-cadherin but not APC or alpha-catenin. (1995) Mol. Cell. Biol. 15: 4819-4824.
- Reynolds AB, Daniel JM, McCrea PD, Wheelock MT, Wu J and Zhang Z. Identification of a new catenin: The tyrosine kinase substrate p120cas associates with E-cadherin complexes. (1994) Mol. Cell. Biol. 14: 8333-8342.
|The long-term research goal of my laboratory is to understand the cellular and molecular basis of cadherin-mediated adhesion in normal cell growth, development and tumourigenesis. In human cancer, it is tumour metastases to vital organs such as the lungs and liver, and not the primary tumour itself that proves fatal. However, despite significant advances in our understanding the underlying principles of tumour initiation, the mechanisms governing tumour progression from the benign to the malignant invasive phase remain poorly understood. Hence a thorough understanding of the factors that regulate and control cell adhesion and motility would significantly facilitate the development of improved cancer therapies. To this end, my laboratory focuses on the primary epithelial cell-cell adhesion system involving E-cadherin and its cytosolic cofactors, the catenins a-, b-, g- and p120ctn. This adhesion system is perturbed in ~50% of human metastatic tumours, and its malfunction correlates with the invasive phenotype. More recently, the catenins were found to also play a role in signal transduction via their transcriptional regulation of target genes involved in tumourigenesis. This alternative mechanism for contributing to tumour malignancy is best exemplified by b-catenin, which interacts with the Lef/TCF family of transcription factors to constitutively activate genes implicated in tumourigenesis (e.g. c-myc, cyclinD1, ID2, matrilysin).
The specific focus of my laboratory is the transcription factor Kaiso that was first identified as a binding partner for the catenin p120ctn, which is aberrantly expressed or absent in human breast, colon and skin carcinomas. Whereas the classical catenins b-catenin and plakoglobin anchor the cadherin-catenin complex to the actin cytoskeleton, p120ctn regulates cell motility and the adhesive strength of the complex by an unknown mechanism that may involve the Rho GTPases. Interestingly, Kaiso interacts specifically with p120ctn but not with b-catenin or any other catenin. Kaiso is a novel member of the POZ-zinc finger family of transcription factors implicated as oncoproteins or tumor suppressors. Currently it is the only known POZ transcriptional repressor with bi-modal DNA-binding and transcriptional repression activity; it recognizes a sequence-specific consensus, TCCTGCNA, and methylated CpG-dinucleotides. Interestingly, both Kaiso’s DNA-binding and transcriptional repression activity are inhibited by p120ctn. Collectively our data implicates Kaiso as an important and interesting transcription factor with potential roles in cell growth, adhesion signaling and tumourigenesis.
|Identification of Kaiso-specific target genes and the characterization of Kaiso transcriptional activity on these target genes|
|Using CAST (cyclic amplification and selection of targets) analysis of a random oligonucleotide library, we identified a sequence-specific Kaiso binding site, TCCTGCNA (Daniel et al. 2002. NAR 30). Interestingly this site was distinct from the methylated CpG-dinucleotide site identified by an independent group. We subsequently confirmed that Kaiso was the first POZ-ZF transcription factor with dual-specificity DNA-binding and transcriptional repression ability (Kelly et al. 2004. J. Cell Sci. 117). Recently we identified the matrilysin gene as a potential Kaiso target; both the human and mouse matrilysin promoters possess two copies of the optimal Kaiso consensus site and we detected matrilysin promoter fragments in Kaiso immunocomplexes. In addition Kaiso repressed a human matrilysin-luciferase reporter ~10 fold. These findings thus support the idea of matrilysin as a Kaiso target gene. Our current experiments are now aimed at (1) determining the correlation between Matrilysin and Kaiso expression in human tumours using tissue microarrays and (2) identification and characterization of other bona fide Kaiso target genes using unbiased ChIP cloning strategies.|
|Characterization of novel Kaiso-binding partners to gain insight on the mechanism of action of Kaiso and elucidate the signaling pathway(s) involving Kaiso|
|The second major project in my laboratory involves a yeast two-hybrid screen to identify additional Kaiso-binding partners. Using the Kaiso POZ domain as bait, we have identified several cytoskeletal proteins and DNA-binding proteins. We are currently validating and characterizing the specificity of the interactions between Kaiso and these proteins using co-precipitation and immunoblot techniques.|
|Elucidation of the mechanism and physiological relevance f nucleocytoplasmic trafficking of Kaiso and p120ctn|
|Another ongoing project in my laboratory is to determine what event or signaling molecule triggers the nuclear translocation of p120ctn and its interaction with Kaiso. Since p120ctn is implicated in cadherin–initiated signaling through the Rho GTPases, one possibility is that p120ctn mediates the long-suspected adhesion signal. While this trigger remains unknown, we have discovered that nuclear p120ctn inhibits Kaiso DNA-binding and negatively regulates Kaiso-mediated transcriptional repression (Kelly et al. 2004. J. Cell Sci. 117). In addition, we recently mapped the Kaiso and p120ctn nuclear localization signals and determined that nuclear localization of p120ctn was required for its inhibitory effect on Kaiso-mediated transcriptional repression (Kelly et al. 2004 J. Cell Sci. 117). Current experiments are aimed at investigating the effects of Kaiso and p120ctn mislocalization on cell growth, adhesion and motility. Collectively these studies will significantly advance our understanding of the biological roles of Kaiso and p120ctn with respect to gene expression, growth control, cadherin-mediated cell adhesion, and tumourigenesis. We anticipate that this knowledge will allow us to determine how malfunction of the cadherin-catenin complex and catenin signaling pathways contribute to the acquisition of the invasive phenotype. In addition our findings may offer promise for the development of therapeutic strategies and animal models for the treatment of malignant tumours.|
|Research in the Daniel laboratory is currently funded by the Canadian Institutes of Health Research (CIHR), the US Department of Defense Congressionally Directed Medical Research Programs IDEA Award (DOD CDMRP), the Canadian Foundation for Innovation (CFI) and the Ontario Innovation Trust (OIT).|